1. Aglinskas A, Schwartz E, Anzellotti S. Disentangling disorder-specific variation is key for precision psychiatry in autism. Frontiers in behavioral neuroscience. 2023; 17: 1121017.

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2. Arun P, Azad C, Kaur G, Sharma P. A Community-Based Study of Antenatal and Neonatal Risk Factors in Autism Spectrum Disorder. The primary care companion for CNS disorders. 2023; 25(2).

Objective: To assess children in the community for autism spectrum disorder (ASD) and associated risk factors. Methods: In this 2-stage, cross-sectional study, children between 1.5 and 10 years of age were screened using the Chandigarh Autism Screening Instrument. Those with a score above the cutoff of 10 were assessed in detail using the Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised, and a detailed pediatric assessment was conducted. Risk factors were evaluated, and karyotype and fragile X genetic testing was done for those diagnosed with ASD. The study was conducted from July 2014 to December 2017. Results: Compared to the control group, mothers of ASD children had more pregnancy-induced hypertension (PIH) and bleeding per vaginum (BPV) during the antenatal period. In the multivariate analysis, there was 6.3 times higher odds of having history of PIH (P = .02) and 7.7 times higher odds of BPV (P = .011) among children with ASD. There were much higher odds of having birth asphyxia (OR = 12.6), cardiorespiratory problems (OR = 10), metabolic abnormalities (hypoglycemia/ hypocalcemia) (OR = 12), and neonatal sepsis (OR = 16) in the ASD group compared to controls. Conclusions: ASD patients experienced more antenatal and neonatal problems compared to controls. Trial Registration: Clinical Trials Registry-India (CTRI/2017/02/007935).

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3. Grönniger B, Danzer A, Kimpe K, Singh A, Sadowski G. Viscoelastic Behavior of Supercooled and Glassy ASDs at Humid Conditions Can Be Predicted. Molecular pharmaceutics. 2023.

Amorphous solid dispersions (ASDs) are commonly used to increase the dissolution rate of poorly soluble active pharmaceutical ingredients (APIs). Unfortunately, most ASDs are thermodynamically unstable and, even though kinetically stabilized, will thus eventually crystallize. The crystallization kinetics is determined by the thermodynamic driving force and by molecular mobility, which in turn depend on the drug load, temperature, and relative humidity (RH) at which the ASDs are stored. This work focuses on viscosity as an indicator for the molecular mobility in ASDs. The viscosity and shear moduli of ASDs consisting of the polymer poly(vinylpyrrolidone-co-vinyl acetate) or hydroxypropyl methylcellulose acetate succinate and the API nifedipine or celecoxib were studied using an oscillatory rheometer. The effects of temperature, drug load, and RH on the viscosity were investigated. With the knowledge of how much water is absorbed by the polymer or ASD and thereby also the knowledge of the glass-transition temperature of the wet polymer or ASD, the viscosity of dry and wet ASDs was predicted to be in very good agreement with experimental data just based on the viscosity of neat polymers and the glass-transition temperatures of wet ASDs.

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4. Hudac CM, Friedman NR, Ward VR, Estreicher RE, Dorsey GC, Bernier RA, Kurtz-Nelson EC, Earl RK, Eichler EE, Neuhaus E. Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability. Journal of autism and developmental disorders. 2023: 1-16.

We aimed to identify unique constellations of sensory phenotypes for genetic etiologies associated with diagnoses of autism spectrum disorder (ASD) and intellectual disability (ID). Caregivers reported on sensory behaviors via the Sensory Profile for 290 participants (younger than 25 years of age) with ASD and/or ID diagnoses, of which ~ 70% have a known pathogenic genetic etiology. Caregivers endorsed poor registration (i.e., high sensory threshold, passive behaviors) for all genetic subgroups relative to an « idiopathic » comparison group with an ASD diagnosis and without a known genetic etiology. Genetic profiles indicated prominent sensory seeking in ADNP, CHD8, and DYRK1A, prominent sensory sensitivities in SCN2A, and fewer sensation avoidance behaviors in GRIN2B (relative to the idiopathic ASD comparison group).

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5. Kumar M, Hiremath C, Khokhar SK, Bansal E, Sagar KJV, Padmanabha H, Girimaji AS, Narayan S, Kishore MT, Yamini BK, Jac Fredo AR, Saini J, Bharath RD. Altered cerebellar lobular volumes correlate with clinical deficits in siblings and children with ASD: evidence from toddlers. Journal of translational medicine. 2023; 21(1): 246.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social and communication skills, narrow interests, and repetitive behavior. It is known that the cerebellum plays a vital role in controlling movement and gait posture. However, recently, researchers have reported that the cerebellum may also be responsible for other functions, such as social cognition, reward, anxiety, language, and executive functions. METHODS: In this study, we ascertained volumetric differences from cerebellar lobular analysis from children with ASD, ASD siblings, and typically developing healthy controls. In this cross-sectional study, a total of 30 children were recruited, including children with ASD (N = 15; mean age = 27.67 ± 5.1 months), ASD siblings (N = 6; mean age = 17.5 ± 3.79 months), and typically developing children (N = 9; mean age = 17.67 ± 3.21 months). All the MRI data was acquired under natural sleep without using any sedative medication. We performed a correlation analysis with volumetric data and developmental and behavioral measures obtained from these children. Two-way ANOVA and Pearson correlation was performed for statistical data analysis. RESULTS: We observed intriguing findings from this study, including significantly increased gray matter lobular volumes in multiple cerebellar regions including; vermis, left and right lobule I-V, right CrusII, and right VIIb and VIIIb, respectively, in children with ASD, compared to typically developing healthy controls and ASD siblings. Multiple cerebellar lobular volumes were also significantly correlated with social quotient, cognition, language, and motor scores with children with ASD, ASD siblings, and healthy controls, respectively. CONCLUSIONS: This research finding helps us understand the neurobiology of ASD and ASD-siblings, and critically advances current knowledge about the cerebellar role in ASD. However, results need to be replicated for a larger cohort from longitudinal research study in future.

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6. Marquis S, Lunsky Y, McGrail KM, Baumbusch J. Population level administrative data evidence of visits to the emergency department by youth with intellectual/developmental disabilities in BC, Canada. The American journal of emergency medicine. 2023; 69: 52-7.

INTRODUCTION: The literature indicates that youth with intellectual/developmental disabilities (IDD) have poor health and that access to health services decreases as they transition from pediatric to adult services. At the same time their use of emergency department services increases. The objective of this study was to compare use of emergency department services by youth with IDD to youth without IDD, with particular emphasis on the transition period from pediatric to adult health care services. METHODS: This research used a population level administrative health data base for the province of British Columbia Canada for 2010-2019 to examine the use of emergency departments by youth with IDD (N = 20,591) compared to a population group of youth without IDD (N = 1,293,791). Using the ten years of data, odds ratios for visits to the emergency department were calculated adjusting for sex, income and geographical area within the Province. In addition, difference-in-differences analyses were calculated for age matched subsets of the two cohorts. RESULTS: Over the ten year period, 40.60% of youth with IDD visited an emergency department at least once, compared to 29.10% of youth without IDD. Youth with IDD had an odds ratio of visiting an emergency department 1.697 (1.649, 1.747) times that of youth without IDD. However, when odds were adjusted for a diagnosis of either psychotic illness or anxiety/depression, the odds for youth with IDD visiting emergency compared to youth without IDD were reduced to 1.063 (1.031, 1.096). Use of emergency services increased as youth aged. Type of IDD also affected use of emergency services. Youth with Fetal Alcohol Syndrome had the greatest odds of using emergency services compared to youth with other types of IDD. DISCUSSION: The findings from this study indicate that youth with IDD have higher odds of using emergency services than youth without IDD although these increased odds appear to be largely driven by mental illness. In addition, use of emergency services increases as the youth age and transition from pediatric to adult health services. Better treatment of mental health issues within this population may reduce their use of emergency services.

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7. Martín R, Suárez-Pinilla AS, García-Font N, Laguna-Luque ML, López-Ramos JC, Oset-Gasque MJ, Gruart A, Delgado-García JM, Torres M, Sánchez-Prieto J. The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome. Molecular autism. 2023; 14(1): 14.

BACKGROUND: Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment. METHODS: We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4. RESULTS: We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca(2+) concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice. LIMITATIONS: We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells. CONCLUSIONS: Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.

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8. Molloy CJ, Quigley C, McNicholas Á, Lisanti L, Gallagher L. A review of the cognitive impact of neurodevelopmental and neuropsychiatric associated copy number variants. Translational psychiatry. 2023; 13(1): 116.

The heritability of intelligence or general cognitive ability is estimated at 41% and 66% in children and adults respectively. Many rare copy number variants are associated with neurodevelopmental and neuropsychiatric conditions (ND-CNV), including schizophrenia and autism spectrum disorders, and may contribute to the observed variability in cognitive ability. Here, we reviewed studies of intelligence quotient or cognitive function in ND-CNV carriers, from both general population and clinical cohorts, to understand the cognitive impact of ND-CNV in both contexts and identify potential genotype-specific cognitive phenotypes. We reviewed aggregate studies of sets ND-CNV broadly linked to neurodevelopmental and neuropsychiatric conditions, and genotype-first studies of a subset of 12 ND-CNV robustly associated with schizophrenia and autism. Cognitive impacts were observed across ND-CNV in both general population and clinical cohorts, with reports of phenotypic heterogeneity. Evidence for ND-CNV-specific impacts were limited by a small number of studies and samples sizes. A comprehensive understanding of the cognitive impact of ND-CNVs would be clinically informative and could identify potential educational needs for ND-CNV carriers. This could improve genetic counselling for families impacted by ND-CNV, and clinical outcomes for those with complex needs.

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9. Mykins M, Layo-Carris D, Dunn LR, Skinner DW, McBryar AH, Perez S, Shultz TR, Willems A, Lau BYB, Hong T, Krishnan K. Wild-type MeCp2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome. Journal of neuroscience research. 2023.

Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2(Heterozygous) , Het) express a functional copy of wild-type MeCp-2 protein in approximately half of all cells. As MeCp2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MeCp2 in the primary somatosensory cortex of female Het mice. Here, we report increased MeCp2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying typical levels of perineuronal net expression in the barrel field subregion of the primary somatosensory cortex, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MeCp2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincides with changes in wild-type MeCp2 expression. We speculate that the precocious increase in MeCp2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MeCp2 levels leads to regressive behavioral phenotypes over time.

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10. Qian M, Lin S, Tan Y, Chen Q, Wang W, Li J, Mu C. A nonsense mutation in the CUL3 gene in a Chinese patient with autism spectrum disorder and epilepsy: A case report. Medicine. 2023; 102(14): e33457.

RATIONALE: CUL3 (OMIM: 603136) encodes cullin-3, a core component of ubiquitin E3 ligase. Existing medical research suggests that CUL3 mutations are closely related to neurodevelopmental disorder with or without autism or seizures (neurodevelopmental disorder with autism and seizures, OMIM: 619239). However, the number of published case reports of autism spectrum disorder due to CUL3 gene mutations is limited. PATIENT CONCERN: A four-year-old Chinese girl presented with generalized epilepsy, and then exhibited developmental regression, including loss of her speaking ability, eye contact aversion, and stereotyped behavior. DIAGNOSES: Whole-exome sequencing identified a nonsense mutation in the CUL3 gene, being c.2065A > T (p.Lys689*); no previous similar case was reported. The final diagnosis was autism, epilepsy, and motor growth retardation. INTERVENTION: In order to improve quality of life of the patient, she was provided with exercise rehabilitation training and autism behavioral guidance therapy for 3 months. OUTCOMES: The patient’s exercise capacity had improved, and improvements in autism symptoms were not obvious. LESSONS: For clinicians, patients with developmental regression accompanied with concurrent epilepsy and autism spectrum disorder should be advised that relevant genetic tests are necessary to clarify the diagnosis.

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11. Rane D, Sharma P, Singh M, Lahiri U. Virtual Reality based Gaze-sensitive Aiming Task Platform: Role of Attention Allocation in Task Performance for Individuals with Autism and Typically Developing Individuals. IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society. 2023; Pp.

Individuals with Autism Spectrum Disorder (ASD) often exhibit difficulty in movement preparation and allocating attention towards different Regions of Interest (ROIs) of a visual stimulus. Though research has alluded to differences in movement preparation for aiming tasks between individuals with ASD and typically developing (TD) individuals, there is limited evidence (true for near-aiming tasks) on the contribution of the window (i.e., time duration) of movement preparation (i.e., the planning window preceding movement initiation) on one’s aiming performance. However, investigation of the contribution of this planning window on one’s performance in far-aiming task remains as majorly unexplored. Again, often one’s eye movement leads the initiation of hand movement (for task execution) indicating the importance of monitoring one’s eye movement in the planning stage, critical for far-aiming task. Most of the studies (in conventional settings) examining the role of gaze behavior on aiming performance have involved TD individuals and only a few involving individuals with ASD. Here, we have designed Virtual Reality (VR)-based Gaze-sensitive far-aiming (dart throw) task and monitored the looking pattern of participants while they interacted with the task environment. We carried out a study with 40 participants (20 in each of ASD and TD groups) to understand how the participant groups differed in task performance and gaze fixation within the movement planning window. We observed difference in the scan path and last fixation within the movement planning window before triggering the release of the dart with relevance to task performance.

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12. Santos JX, Sampaio P, Rasga C, Martiniano H, Faria C, Café C, Oliveira A, Duque F, Oliveira G, Sousa L, Nunes A, Vicente AM. Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder. Environmental research. 2023; 228: 115795.

Early-life exposure to air pollutants, including ozone (O(3)), particulate matter (PM(2.5) or PM(10), depending on diameter of particles), nitrogen dioxide (NO(2)) and sulfur dioxide (SO(2)) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM(2.5), PM(10) and NO(2) to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM(2.5) and PM(10) above the admissible threshold. A higher clinical severity was associated with higher exposure to PM(2.5) (p = 0.001), NO(2) (p = 0.011) and PM(10) (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM(2.5) exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05-1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00-1.15) and for PM(10) (p = 0.02; OR = 1.07, 95%CI: 1.01-1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of early-life exposure to PM in ASD clinical severity.

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13. Wahdan MM, Malak MZ, Al-Amer R, Ayed A, Russo S, Berte DZ. Effect of incredible years autism spectrum and language delays (IY-ASD) program on stress and behavioral management skills among parents of children with autism spectrum disorder in Palestine. Journal of pediatric nursing. 2023; 72: 45-52.

PURPOSE: This study purposed to evaluate the effect of the Incredible Years Autism Spectrum and Language Delays (IY-ASD) program in reducing parents’ stress and improving aggressive and disruptive behaviors in the parents among parents of children with autism spectrum disorder in Palestine. DESIGN AND METHODS: A one-group pre-posttest design was used. Thirty-four parents who enrolled in the Palestinian Child Institute in Nablus were recruited. RESULTS: Findings revealed a significant difference between parents’ total stress pre and post-IY-ASD (t = 1.2, p < 0.01 and parents' behavioral management skills toward their children with autism spectrum disorder. The study demonstrated that the IY-ASD program for 16 sessions reduced stress among parents of children with autism spectrum disorder in Palestine and improved aggressive and disruptive behaviors in the parents. CONCLUSION: The IY-ASD program can be successfully implemented for parents of this cohort group. PRACTICE IMPLICATIONS: Healthcare providers can adopt such a program for enhancing parenting roles with their children experiencing autism spectrum disorder.

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